Nanotechnology Enhanced RNAi Therapies in Cancer: A Systematic Review

Authors

  • Muhammad Abid Mustafa Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Lahore University of Biological and Applied Sciences, Lahore, Pakistan
  • Namra Rasheed Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Lahore University of Biological and Applied Sciences, Lahore, Pakistan

DOI:

https://doi.org/10.62382/jcbt.v2i4.80

Keywords:

Small interfering RNA, Polymeric and lipid nanoparticles, Precision oncology, Stimuli-responsive delivery, Gene silencing, Clinical and preclinical research

Abstract

Cancer remains a major cause of illness and death worldwide, with conventional treatments often hindered by systemic toxicity, lack of specificity, and the development of resistance. RNA interference (RNAi) provides a highly targeted approach to silencing cancer-causing genes and disrupted signalling pathways, laying the groundwork for precision cancer treatment. Although it holds great promise, clinical use of RNAi is currently limited by poor stability, rapid breakdown in the blood, limited cell uptake, entrapment in endosomes, and barriers within the tumour microenvironment. Nanotechnology-based delivery systems have become a key strategy for overcoming these challenges, enhancing RNAi stability, promoting targeted tumour accumulation, facilitating efficient cell internalisation, and enabling controlled release within cells. This review provides a comprehensive assessment of the biological basis of RNAi, the obstacles to its effective use, and the various types of nanocarriers developed to improve therapeutic outcomes. Combination approaches combining RNAi with chemotherapy, immunotherapy, and gene editing are also explored, alongside advances in passive and active tumour targeting. A summary of preclinical and clinical data proving the pharmacokinetic benefits, safety, and effectiveness of nanocarrier-assisted RNA interference is provided.  Finally, new developments, including patient-specific RNAi treatments, biodegradable and intelligent nanomaterials, and integration with biomarker-driven tactics, are emphasised. This review highlights the revolutionary potential of RNA interference (RNAi) enhanced by nanotechnology for safe, accurate, and efficient cancer treatment, while also pointing to directions for further translational research.

Downloads

Download data is not yet available.

References

American Cancer Society. Global Cancer Facts & Figures, 4th ed, American Cancer Society: Atlanta, GA, USA, 2023.

World Health Organization; American Cancer Society. Global Cancer Burden Growing Amidst Mounting Need for Services. Global Cancer Facts & Figures, 4th ed, WHO: Geneva, Switzerland, 2024.

Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA: A Cancer Journal for Clinicians. 2024, 74(1), 12-49. DOI: 10.3322/caac.21820

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2021, 71(3), 209-249. DOI: 10.3322/caac.21660

Singh J, Saeedan AS, Kaithwas G, Ansari MN. Small interfering RNA: From designing to therapeutic in cancer. Journal of Genetic Engineering and Biotechnology. 2025, 23(2), 100484. DOI: https://doi.org/10.1016/j.jgeb.2025.100484

Setten RL, Rossi JJ, Han SP. The current state and future directions of RNAi-based therapeutics. Nature Reviews Drug Discovery. 2019, 18(6), 421-446. DOI: 10.1038/s41573-019-0017-4

Kulkarni JA, Witzigmann D, Thomson SB, Chen S, Leavitt BR, Cullis PR, et al. The current landscape of nucleic acid therapeutics. Nature Nanotechnology. 2021, 16(6), 630-643. DOI: 10.1038/s41565-021-00898-0

Sharma A, Jha NK, Dahiya K, Singh VK, Chaurasiya K, Jha AN, et al. Nanoparticulate RNA delivery systems in cancer. Cancer Reports. 2020, 3(5), e1271. DOI: 10.1002/cnr2.1271

Blanco E, Shen HF, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nature Biotechnology. 2015, 33(9), 941-951. DOI: 10.1038/nbt.3330

Ammar MM, Ali R, Abd Elaziz NA, Habib H, Abbas FM, Yassin MT, et al. Nanotechnology in oncology: Advances in biosynthesis, drug delivery, and theranostics. Discover Oncology. 2025, 16(1), 1172. DOI: 10.1007/s12672-025-02664-3

Zhang JY, Chen B, Gan CY, Sun HY, Zhang JX, Feng L. A comprehensive review of small interfering RNAs (siRNAs): Mechanism, therapeutic targets, and delivery strategies for cancer therapy. International Journal of Nanomedicine. 2023, 18, 7605-7635. DOI: 10.2147/IJN.S436038

Huang R, Du H, Cheng L, Zhang PZ, Meng FH, Zhong ZY. Targeted nanodelivery of siRNA against KRAS G12D inhibits pancreatic cancer. Acta Biomaterialia. 2023, 168, 529-539. DOI: 10.1016/j.actbio.2023.07.008

Hareddy YS, Huggins HP, Sahoo SS, Stanland L, Gutierrez-Ford C, Whately KM, et al. Inverted chimeric RNAi molecules synergistically co-target MYC and KRAS in KRAS-driven cancers. The Journal of Clinical Investigation. 2025, 135(19), e187204. DOI: 10.1172/JCI187204

Zaidi SA, Fatima F, Zaidi SA, Zhou DZ, Deng WQ, Liu S. Engineering siRNA therapeutics: Challenges and strategies. Journal of Nanobiotechnology. 2023, 21(1), 381. DOI: 10.1186/s12951-023-02147-z

Kurakula H, Vaishnavi S, Sharif MY, Ellipilli S. Emergence of small interfering RNA-based gene drugs for various diseases. ACS Omega. 2023, 8(23), 20234-20250. DOI: 10.1021/acsomega.3c01703

Ebenezer O, Oyebamiji AK, Olanlokun JO, Tuszynski JA, Wong GK. Recent update on siRNA therapeutics. International Journal of Molecular Sciences. 2025, 26(8), 3456. DOI: 10.3390/ijms26083456

Seth S, Johns R, Templin MV. Delivery and biodistribution of siRNA for cancer therapy: Challenges and future prospects. Therapeutic Delivery. 2012, 3(2), 245-261. DOI: 10.4155/tde.11.155

Huang JX, Xiao K. Nanoparticles-based strategies to improve the delivery of therapeutic small interfering RNA in precision oncology. Pharmaceutics. 2022, 14(8), 1586. DOI: 10.3390/pharmaceutics14081586

Sajid MI, Moazzam M, Kato S, Yeseom Cho K, Tiwari RK. Overcoming Barriers for siRNA Therapeutics: From Bench to Bedside. Pharmaceuticals. 2020, 13(10), 294. DOI: 10.3390/ph13100294

Gao Y, Liu XL, Li XR. Research progress on siRNA delivery with nonviral carriers. International Journal of Nanomedicine. 2011, 6, 1017-1025. DOI: 10.2147/IJN.S17040

Gao S, Dagnaes-Hansen F, Bech Nielsen EJ, Wengel J, Besenbacher F, Howard KA, et al. The effect of chemical modification and nanoparticle formulation on stability and biodistribution of siRNA in mice. Molecular Therapy : the Journal of the American Society of Gene Therapy. 2009, 17(7), 1225-1233. DOI: 10.1038/mt.2009.91

Lee JW, Shim MK, Kim H, Jang H, Lee YH, Kim SH. RNAi therapies: Expanding applications for extrahepatic diseases and overcoming delivery challenges. Advanced Drug Delivery Reviews. 2023, 201, 115073. DOI: 10.1016/j.addr.2023.115073

Guo F, Li Y, Yu WJ, Fu YL, Zhang J, Cao HQ. Recent progress of small interfering RNA delivery on the market and clinical stage. Molecular Pharmaceutics. 2024, 21(5), 2081-2096. DOI: 10.1021/acs.molpharmaceut.3c01158

Moazzam M, Zhang MJ, Hussain A, Yu XT, Huang J, Huang YY. The landscape of nanoparticle-based siRNA delivery and therapeutic development. Molecular therapy : the Journal of the American Society of Gene Therapy. 2024, 32(2), 284-312. DOI: 10.1016/j.ymthe.2024.01.005

Zhao Y, Wang ZM, Song DH, Chen MT, Xu QB. Rational design of lipid nanoparticles: Overcoming physiological barriers for selective intracellular mRNA delivery. Current Opinion in Chemical Biology. 2024, 81, 102499. DOI: 10.1016/j.cbpa.2024.102499

Dowdy SF. Endosomal escape of RNA therapeutics: How do we solve this rate-limiting problem? RNA. 2023, 29(4), 396-401. DOI: 10.1261/rna.079507.122

Motamedi H, Ari MM, Alvandi A, Abiri R. Principle, application and challenges of development siRNA-based therapeutics against bacterial and viral infections: A comprehensive review. Frontiers in Microbiology. 2024, 15, 1393646. DOI: 10.3389/fmicb.2024.1393646

Hou XC, Zaks T, Langer R, Dong YZ. Lipid nanoparticles for mRNA delivery. Nature Reviews Materials. 2021, 6(12), 1078-1094. DOI: 10.1038/s41578-021-00358-0

Ding L, Agrawal P, Singh SK, Chhonker YS, Sun J, Murry DJ. Polymer-based drug delivery systems for cancer therapeutics. Polymers. 2024, 16(6), 843. DOI: 10.3390/polym16060843

Andretto V, Dusi S, Zilio S, Repellin M, Kryza D, Ugel S, et al. Tackling TNF-α in autoinflammatory disorders and autoimmune diseases: From conventional to cutting edge in biologics and RNA-based nanomedicines. Advanced Drug Delivery Reviews. 2023, 201, 115080. DOI: 10.1016/j.addr.2023.115080

Xu H, Zuo S, Wang D, Zhang Y, Li W, Li L, et al. Cabazitaxel prodrug nanoassemblies with branched chain modifications: Narrowing the gap between efficacy and safety. Journal of Controlled Release. 2023, 360, 784-795. DOI: 10.1016/j.jconrel.2023.07.012

Jain S, Jindal AB. Long-acting therapeutics: Development strategies and clinical significance. Advanced Drug Delivery Reviews. 2024, 205, 115163. DOI: 10.1016/j.addr.2023.115163

Chen H, Xing C, Lei H, Yan B, Zhang H, Tong T, et al. ROS-driven supramolecular nanoparticles exhibiting efficient drug delivery for chemo/chemodynamic combination therapy for cancer treatment. Journal of Controlled Release. 2024, 368, 637-649. DOI: 10.1016/j.jconrel.2024.03.015

Choi Y, Seok SH, Yoon HY, Ryu JH, Kwon IC. Advancing cancer immunotherapy through siRNA-based gene silencing for immune checkpoint blockade. Advanced Drug Delivery Reviews. 2024, 209, 115306. DOI: 10.1016/j.addr.2024.115306

Sun XQ, Liu Z. Engineering CRISPR for emerging therapeutic applications. EngMedicine. 2024, 1(3), 100035. DOI: 10.1016/j.engmed.2024.100035

Li X, Peng X, Zoulikha M, Boafo GF, Magar KT, Ju Y, et al. Multifunctional nanoparticle-mediated combining therapy for human diseases. Signal Transduction and Targeted Therapy. 2024, 9(1), 1. DOI: 10.1038/s41392-023-01668-1

Venturini J, Chakraborty A, Baysal MA, Tsimberidou AM. Developments in nanotechnology approaches for the treatment of solid tumors. Experimental Hematology & Oncology. 2025, 14(1), 76. DOI: 10.1186/s40164-025-00656-1

Nabih NW, Hassan HAFM, Preis E, Schaefer J, Babker A, Abbas AM, et al. Antibody-functionalized lipid nanocarriers for RNA-based cancer gene therapy: Advances and challenges in targeted delivery. Nanoscale Advances. 2025, 7(19), 5905-5931. DOI: 10.1039/d5na00323g

An J, Zhou Q, Chu K, Chen S, Niu C, Zhang W, et al. Tumor microenvironment-responsive precise delivery nanocarrier potentiating synchronous radionuclide therapy and chemotherapy against cancer. Journal of Nanobiotechnology. 2025, 23(1), 290. DOI: 10.1186/s12951-025-03364-4

Xu XD, Saw PE, Tao W, Li YJ, Ji XY, Yu M, et al. Tumor Microenvironment-Responsive Multistaged Nanoplatform for Systemic RNAi and Cancer Therapy. Nano Letters. 2017, 17(7), 4427-4435. DOI: 10.1021/acs.nanolett.7b01571

Zhao G, Ho W, Chu J, Xiong X, Hu B, Boakye-Yiadom KO, et al. Inhalable siRNA nanoparticles for enhanced tumor-targeting treatment of KRAS-mutant non-small-cell lung cancer. ACS Applied Materials & Interfaces. 2023, 15(26), 31273-31284. DOI: 10.1021/acsami.3c05007

Hattab D, Gazzali AM, Bakhtiar A. Clinical advances of siRNA-based nanotherapeutics for cancer treatment. Pharmaceutics. 2021, 13(7), 1009. DOI: 10.3390/pharmaceutics13071009

Lv Z, Dai Y. mRNA vaccines and siRNAs targeting cancer immunotherapy: Challenges and opportunities. Discover Oncology. 2025, 16(1), 1265. DOI: 10.1007/s12672-025-03070-5

Sharma S, Parveen R, Chatterji BP. Toxicology of nanoparticles in drug delivery. Current Pathobiology Reports. 2021, 9(4), 133-144. DOI: 10.1007/s40139-021-00227-z

Paunovska K, Loughrey D, Dahlman JE. Drug delivery systems for RNA therapeutics. Nature Reviews. Genetics. 2022, 23(5), 265-280. DOI: 10.1038/s41576-021-00439-4

An G. Pharmacokinetics and pharmacodynamics of GalNAc-conjugated siRNAs. Journal of Clinical Pharmacology. 2024, 64(1), 45-57. DOI: 10.1002/jcph.2337

Alagia A, Eritja R. siRNA and RNAi optimization. Wiley Interdisciplinary Reviews. RNA. 2016, 7(3), 316-329. DOI: 10.1002/wrna.1337

Chan A, Kirtane AR, Qu QR, Huang X, Woo J, Subramanian DA, et al. Designing lipid nanoparticles using a transformer-based neural network. Nature Nanotechnology. 2025. DOI: 10.1038/s41565-025-01975-4

Kato T, Lee D, Huang H, Cruz W, Ujiie H, Fujino K, et al. Personalized siRNA-nanoparticle systemic therapy using metastatic lymph node specimens obtained with EBUS-TBNA in lung cancer. Molecular Cancer Research. 2018, 16(1), 47-57. DOI: 10.1158/1541-7786.MCR-16-0341

Nsairat H, Lafi Z, Al-Najjar BO, Al-Samydai A, Saqallah FG, El-Tanani M, et al. How advanced are self-assembled nanomaterials for targeted drug delivery? A comprehensive review of the literature. International Journal of Nanomedicine. 2025, 20, 2133-2161. DOI: 10.2147/IJN.S490444

Ma L, Guo H, Zhao Y, Liu Z, Wang C, Bu J, et al. Liquid biopsy in cancer: Current status, challenges and future prospects. Signal Transduction and Targeted Therapy. 2024, 9(1), 336. DOI: 10.1038/s41392-024-02021-w

Zhang X, Chan HW, Shao Z, Wang Q, Chow S, Chow SF. Navigating translational research in nanomedicine: A strategic guide to formulation and manufacturing. International Journal of Pharmaceutics. 2025, 671, 125202. DOI: 10.1016/j.ijpharm.2025.125202

Hoang CNM, Nguyen SH, Tran MT. Nanoparticles in cancer therapy: Strategies to penetrate and modulate the tumor microenvironment-A review. Smart Materials in Medicine. 2025, 6(2), 270-284. DOI: 10.1016/j.smaim.2025.07.004

Venturini J, Chakraborty A, Baysal MA, Tsimberidou AM. Developments in nanotechnology approaches for the treatment of solid tumors. Experimental Hematology & Oncology. 2025, 14(1), 76. DOI: 10.1186/s40164-025-00656-1

Wang B, Hu S, Teng Y, Chen J, Wang H, Xu Y, et al. Current advance of nanotechnology in diagnosis and treatment for malignant tumors. Signal Transduction and Targeted Therapy. 2024, 9(1), 200. DOI: 10.1038/s41392-024-01889-y

Downloads

Published

2025-10-13

How to Cite

Mustafa, M. A., & Namra Rasheed. (2025). Nanotechnology Enhanced RNAi Therapies in Cancer: A Systematic Review. Journal of Cancer Biomoleculars and Therapeutics, 2(4), 11–26. https://doi.org/10.62382/jcbt.v2i4.80